DECREASED FOLYLPOLYGLUTAMATE SYNTHETASE-ACTIVITY IN TUMORS RESISTANT TO FLUOROURACIL FOLINIC ACID TREATMENT - CLINICAL-DATA

Thymidylate synthase (TS) is the main target for fluorouracil (FU), Op timal cellular concentrations of reduced folates in polyglutamated for ms [via folylpolyglutamate synthetase (FPGS)] are necessary for achiev ing maximal TS inhibition, The aim of this multicentric prospective st udy was to analyze the link between clinical response to FU therapy fo r liver metastases of colorectal carcinoma and tumoral TS and FPGS act ivities, Forty-four advanced colorectal cancer patients (15 women and 29 men; median age 63, range, 27-78 years) receiving a standard FU-fol inic acid protocol were included, A single hepatic tumoral biopsy was obtained systematically at the time of diagnosis, For 24 patients, a b iopsy in the primary colon tumor was available, TS and FPGS activities were measured by radioenzymatic assays, Clinical response on hepatic metastases was 1 complete response, 12 partial responses, 14 stabiliza tions, and 17 progressions, In hepatic biopsies, TS activity (median, 185; range, <10-3111 fmol/min/mg protein) and FPGS activity (median, 1 270; range, <400-3730 fmol/min/mg protein) exhibited a wide variabilit y, TS activity in primary tumors (median, 461; range, 35-2565 fmol/min /mg protein) was significantly higher than in hepatic metastases, No d ifference was observed between primaries and metastases for FPGS. FPGS activity expressed in liver metastases was significantly correlated t o that expressed in primaries, The distribution of TS activity in live r metastases was not significantly different between responsive and no nresponsive patients, However, FPGS activity measured in liver metasta ses was significantly higher in responsive patients (median, 1550 fmol /min/mg protein) than in nonresponsive patients (median, 1100 fmol/min /mg protein), A discriminant analysis revealed that 24 of the 25 patie nts exhibiting a liver FPGS activity less than or equal to 1100 fmol/m in/mg protein and/or a liver TS >320 fmol/min/mg protein were nonrespo nding patients, These data establish for the first time the potential importance of tumoral FPGS activity for assessing FU-folinic acid resp onsiveness in the clinical setting.